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Antimicrobial Agents and Chemotherapy, November 2007, p. 3948-3959, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01007-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Global Phenotype Screening and Transcript Analysis Outlines the Inhibitory Mode(s) of Action of Two Amphibian-Derived, -Helical, Cationic Peptides on Saccharomyces cerevisiae ^,

C. Oliver Morton,¹ Andrew Hayes,² Michael Wilson,^2, Bharat M. Rash,² Stephen G. Oliver,² and Peter Coote^1*

Centre for Biomolecular Sciences, School of Biology, University of St. Andrews, The North Haugh, St. Andrews KY16 9ST, United Kingdom,¹ Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom²

Received 1 August 2007/ Returned for modification 27 August 2007/ Accepted 29 August 2007

Dermaseptin S3(1-16) [DsS3(1-16)] and magainin 2 (Mag 2) are two unrelated, amphibian-derived cationic peptides that adopt an -helical structure within microbial membranes and have been proposed to kill target organisms via membrane disruption. Using a combination of global deletion mutant library phenotypic screening, expression profiling, and physical techniques, we have carried out a comprehensive in vitro analysis of the inhibitory action of these two peptides on the model fungus Saccharomyces cerevisiae. Gene ontology profiling (of biological processes) was used to identify both common and unique effects of each peptide. Resistance to both peptides was conferred by genes involved in telomere maintenance, chromosome organization, and double-strand break repair, implicating a common inhibitory action of DNA damage. Crucially, each peptide also required unique genes for maintaining resistance; for example, DsS3(1-16) required genes involved in protein targeting to the vacuole, and Mag 2 required genes involved in DNA-dependent DNA replication and DNA repair. Thus, DsS3(1-16) and Mag 2 have both common and unique antifungal actions that are not simply due to membrane disruption. Physical techniques revealed that both peptides interacted with DNA in vitro but in subtly different ways, and this observation was supported by the functional genomics experiments that provided evidence that both peptides also interfered with DNA integrity differently in vivo. This implies that both peptides are able to pass through the cytoplasmic membrane of yeast cells and damage DNA, an inhibitory action that has not been previously attributed to either of these peptides.

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* Corresponding author. Mailing address: Centre for Biomolecular Sciences, School of Biology, University of St. Andrews, The North Haugh, St. Andrews KY16 9ST, United Kingdom. Phone: (44) (0)1334 463406. Fax: (44) (0)1334 462595. E-mail: pjc5{at}st-andrews.ac.uk

Published ahead of print on 10 September 2007.

Supplemental material for this article may be found at http://aac.asm.org/.

Present address: Centre for Plant Integrative Biology, School of Biosciences, University of Nottingham, Sutton Bonington LE12 5RD, United Kingdom.

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Antimicrobial Agents and Chemotherapy, November 2007, p. 3948-3959, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01007-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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